Abstract:
:Histone deacetylase (HDAC) inhibitors (HDACis) have demonstrated activity in hematological and solid malignancies. Vorinostat, romidepsin, belinostat, and panobinostat are Food and Drug Administration-approved for hematological malignancies and inhibit class II and/or class I HDACs, including HDAC1, 2, 3, and 6. We combined genetic and pharmacological approaches to investigate whether suppression of individual or multiple Hdacs phenocopied broad-acting HDACis in 3 genetically distinct leukemias and lymphomas. Individual Hdacs were depleted in murine acute myeloid leukemias (MLL-AF9;Nras(G12D); PML-RARα acute promyelocytic leukemia [APL] cells) and Eµ-Myc lymphoma in vitro and in vivo. Strikingly, Hdac3-depleted cells were selected against in competitive assays for all 3 tumor types. Decreased proliferation following Hdac3 knockdown was not prevented by BCL-2 overexpression, caspase inhibition, or knockout of Cdkn1a in Eµ-Myc lymphoma, and depletion of Hdac3 in vivo significantly reduced tumor burden. Interestingly, APL cells depleted of Hdac3 demonstrated a more differentiated phenotype. Consistent with these genetic studies, the HDAC3 inhibitor RGFP966 reduced proliferation of Eµ-Myc lymphoma and induced differentiation in APL. Genetic codepletion of Hdac1 with Hdac2 was pro-apoptotic in Eµ-Myc lymphoma in vitro and in vivo and was phenocopied by the HDAC1/2-specific agent RGFP233. This study demonstrates the importance of HDAC3 for the proliferation of leukemia and lymphoma cells, suggesting that HDAC3-selective inhibitors could prove useful for the treatment of hematological malignancies. Moreover, our results demonstrate that codepletion of Hdac1 with Hdac2 mediates a robust pro-apoptotic response. Our integrated genetic and pharmacological approach provides important insights into the individual or combinations of HDACs that could be prioritized for targeting in a range of hematological malignancies.
journal_name
Bloodjournal_title
Bloodauthors
Matthews GM,Mehdipour P,Cluse LA,Falkenberg KJ,Wang E,Roth M,Santoro F,Vidacs E,Stanley K,House CM,Rusche JR,Vakoc CR,Zuber J,Minucci S,Johnstone RWdoi
10.1182/blood-2015-03-632984subject
Has Abstractpub_date
2015-11-19 00:00:00pages
2392-403issue
21eissn
0006-4971issn
1528-0020pii
blood-2015-03-632984journal_volume
126pub_type
杂志文章相关文献
BLOOD文献大全abstract::Posttransplantation lymphoproliferative disease (PTLD) associated with Epstein-Barr virus (EBV) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation. PTLD is efficiently prevented by adoptive transfer of EBV-specific T cells from the donor. To make EBV-specific T cells available ...
journal_title:Blood
pub_type: 临床试验,杂志文章,多中心研究
doi:10.1182/blood-2009-08-236356
更新日期:2010-04-08 00:00:00
abstract::A new human leukemia cell line, designated as ME-1, was established from the peripheral blood leukemia cells of a patient with acute myelomonocytic leukemia with eosinophilia (M4E0). This cell line has the characteristic chromosome abnormality of M4E0, inv(16) (p13q22). When cultured in RPMI 1640 medium containing 10%...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1991-07-15 00:00:00
abstract::The U-A10 cell line, a doxorubicin-selected variant of human U-937 myeloid leukemia cells, exhibits a redistribution of anthracyclines into a expanded vesicular compartment. The acidic nature of this compartment was confirmed by vital staining with a pH sensitive dye, LysoSensor yellow/blue DND-160. Identification of ...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1997-05-15 00:00:00
abstract::Prediagnostic serum concentration of soluble CD30 (sCD30), a marker for chronic B-cell stimulation, has been associated with increased risk of developing AIDS-related non-Hodgkin lymphoma (NHL) in a recent study of HIV(+) patients. To investigate among healthy persons whether serum sCD30 is associated with NHL risk, w...
journal_title:Blood
pub_type: 杂志文章,多中心研究
doi:10.1182/blood-2009-04-217521
更新日期:2009-09-24 00:00:00
abstract::Conflicting data have been reported on the risk for venous thrombosis in subjects with low free protein S levels. We performed a post-hoc analysis in a single-center retrospective thrombophilic family cohort, to define the optimal free protein S level that can identify subjects at risk for venous thrombosis. Relatives...
journal_title:Blood
pub_type: 临床试验,杂志文章,多中心研究
doi:10.1182/blood-2008-08-174128
更新日期:2009-02-05 00:00:00
abstract::The frequent occurrence of TF gene involvement in translocations associated with leukemia is remarkable, although not yet explained. The wide variety of TFs involved in these translocations and the different stages of cellular maturation argue against a unifying mechanism. Recombinases, active during B-cell and T-cell...
journal_title:Blood
pub_type: 杂志文章,评审
doi:
更新日期:1992-12-15 00:00:00
abstract::Marginal zone B-cell lymphoma (MZL) is a recently individualized lymphoma that encompasses mucosa-associated lymphoid tissue (MALT) lymphoma, splenic lymphoma with or without villous lymphocytes, and nodal lymphoma with or without monocytoid B-cells. If the clinical description and outcome of MALT lymphoma is well kno...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:2000-03-15 00:00:00
abstract::FLT3-ITD+ acute myeloid leukemia (AML) accounts for ∼25% of all AML cases and is a subtype that carries a poor prognosis. microRNA-155 (miR-155) is specifically overexpressed in FLT3-ITD+ AML compared with FLT3 wild-type (FLT3-WT) AML and is critical for the growth of FLT3-ITD+ AML cells in vitro. However, miR-155's r...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2016-09-740209
更新日期:2017-06-08 00:00:00
abstract::The majority of diffuse large B-cell lymphoma (DLBCL) tumors contain mutations in histone-modifying enzymes (HMEs), indicating a potential therapeutic benefit of histone deacetylase inhibitors (HDIs), and preclinical data suggest that HDIs augment the effect of rituximab. In this randomized phase 2 study, we evaluated...
journal_title:Blood
pub_type: 杂志文章,多中心研究
doi:10.1182/blood-2016-02-699520
更新日期:2016-07-14 00:00:00
abstract::Identification of the regulatory inputs that direct megakaryocytopoiesis and platelet production is essential for the development of novel therapeutic strategies for the treatment of thrombosis and related hematologic disorders. We have previously shown that primary human megakaryocytes express the N-methyl-d-aspartat...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2002-11-3553
更新日期:2003-08-15 00:00:00
abstract::The platelet release reaction plays a critical role in thrombosis and contributes to the events that follow hemostasis. Previous studies have shown that platelet secretion is mediated by Soluble NSF Attachment Protein Receptor (SNARE) proteins from granule and plasma membranes. The SNAREs form transmembrane complexes ...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2012-05-430603
更新日期:2012-09-20 00:00:00
abstract::The human burst-forming unit-megakaryocyte (BFU-MK) is a primitive megakaryocytic progenitor cell. A marrow cell population enriched for BFU-MK (CD34+ DR-) was obtained by monoclonal antibody labeling and fluorescence-activated cell sorting. CD34+DR- cells were assayed in a serum-depleted, fibrin clot culture system. ...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1990-08-01 00:00:00
abstract::Antigenic stimulation through the B-cell antigen receptor (BCR) is considered to promote the expansion of chronic lymphocytic leukemia (CLL) B cells. The spleen tyrosine kinase (Syk), a key component of BCR signaling, can be blocked by R406, a small-molecule Syk inhibitor, that displayed activity in CLL patients in a ...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2009-03-212837
更新日期:2009-07-30 00:00:00
abstract::We previously showed that granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) stimulate the differentiation of human monocytes into two phenotypically distinct types of macrophages. However, in vivo, not only CSF but also many other cytokines are produced under va...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1996-11-15 00:00:00
abstract::The mevalonate pathway produces many critical substances in cells, including sterols essential for membrane structure and isoprenoids vital to the function of many membrane proteins. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase is a rate-limiting enzyme in the mevalonate pathway. Because cholesterol is a ...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2002-07-2283
更新日期:2003-05-01 00:00:00
abstract::Depressed cellular immune function and increased susceptibility to infection characterize familial erythrophagocytic lymphohistiocytosis (FEL), a usually fatal autosomal recessive disease. One component of the immunodeficiency is plasma-mediated inhibition of lymphocyte proliferation. We have tested whether repeated p...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1982-10-01 00:00:00
abstract::Autoimmune hemolytic anemia (AIHA) in children is sometimes characterized by a severe course, requiring prolonged administration of immunosuppressive therapy. Rituximab is able to cause selective in vivo destruction of B lymphocytes, with abrogation of antibody production. In a prospective study, we have evaluated the...
journal_title:Blood
pub_type: 临床试验,杂志文章
doi:10.1182/blood-2002-11-3547
更新日期:2003-05-15 00:00:00
abstract::The administration of interleukin-2 (IL-2) may induce complete remissions in acute myelogenous leukemia (AML) patients with a low proportion of residual bone marrow (BM) blasts. To confirm this preliminary observation, we treated 14 AML patients with advanced disease and with a residual BM blastosis that ranged betwee...
journal_title:Blood
pub_type: 临床试验,杂志文章
doi:
更新日期:1994-10-01 00:00:00
abstract::Recently various genetic defects in immunity mediated by interferon gamma (IFN-gamma) have been described, including mutations in the IFN-gamma receptor 1 (IFN-gammaR1) and receptor 2 (IFN-gammaR2), signal transducer and activator of transcription 1 (STAT 1), and interleukin 12 receptor beta 1 (IL-12Rbeta1), and IL-12...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2003-04-1065
更新日期:2004-01-15 00:00:00
abstract::Patients after allogeneic stem-cell transplantation (alloSCT) have an increased risk for invasive aspergillosis (IA). Here, recipients of an allograft with IA (n=81) or without IA (n=58) were screened for 84 single nucleotide polymorphisms in 18 immune relevant genes. We found 3 markers in chemokine (C-X-C motif) liga...
journal_title:Blood
pub_type: 杂志文章,多中心研究
doi:10.1182/blood-2007-05-090928
更新日期:2008-01-15 00:00:00
abstract::Mutations in the kinase domain (KD) of BCR-ABL are the most prevalent mechanism of acquired imatinib resistance in patients with chronic myeloid leukemia (CML). Here we examine predisposing factors underlying acquisition of KD mutations, evidence for acquisition of mutations before and during therapy, and whether the ...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2007-03-066936
更新日期:2007-10-01 00:00:00
abstract::To identify potential mutations in the gamma-glutamyl carboxylase gene, the sequence of all exons and intron/exon borders was determined in 4 patients from a consanguineous kindred with combined deficiency of all vitamin K-dependent procoagulants and anticoagulants and results were compared with normal genomic sequenc...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1998-12-15 00:00:00
abstract::One obstacle to retrovirus-mediated gene therapy for human hematopoietic disorders is the low efficiency of gene transfer into pluripotent hematopoietic stem cells (HSC). We have previously shown a direct correlation between retrovirus receptor mRNA levels in mouse HSC and the efficiency with which they are transduced...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1998-05-01 00:00:00
abstract::Chronic myelogenous leukemia (CML) is a malignant disease of the hematopoietic stem cell characterized by abnormal circulation and proliferation of malignant progenitors. In contrast to their normal counterparts, CML progenitors adhere poorly to bone marrow stroma or fibronectin (FN). Aside from anchoring progenitors ...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1996-03-15 00:00:00
abstract::Neutrophils exposed to fluoride ion (F-) respond with a delayed and sustained burst of superoxide anion release that is both preceded by and dependent on the influx of Ca2+ from the extracellular medium. The results of this study demonstrate a similarly delayed and sustained generation of 1,2-diglyceride in F(-)-treat...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1991-06-15 00:00:00
abstract::Several patients with clinical features of chronic myeloid leukemia (CML) have fusion of the TEL (ETV6) gene on 12p13 with ABL on 9q34 and express a chimeric Tel-Abl protein that contains the same portion of the Abl tyrosine kinase fused to Tel, an Ets family transcription factor, rather than Bcr. In a murine retrovir...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2001-12-0244
更新日期:2002-06-15 00:00:00
abstract::Since its approval in 2011, the Janus kinase 1/2 (JAK1/2) inhibitor ruxolitinib has evolved to become the centerpiece of therapy for myelofibrosis (MF), and its use in patients with hydroxyurea resistant or intolerant polycythemia vera (PV) is steadily increasing. Several other JAK2 inhibitors have entered clinical te...
journal_title:Blood
pub_type: 杂志文章,评审
doi:10.1182/blood-2017-04-742288
更新日期:2017-07-13 00:00:00
abstract::Autologous stem-cell transplantation has become a widely used therapy in Hodgkin's disease (HD). To appreciate the early and late risks associated with this procedure, its lethal toxicity and effects on the incidence of secondary cancers were studied. Data related to 467 French patients grafted from 1982 to 1995 for p...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1998-09-15 00:00:00
abstract::Vascular tube morphogenesis requires the establishment of endothelial cell (EC) apical-basal polarity in three-dimensional (3D) extracellular matrices. To date, there is little understanding of how EC polarity is controlled during these highly dynamic and rapid morphogenic events. We show that the microtubule tip comp...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2012-11-470179
更新日期:2013-04-25 00:00:00
abstract::To study outcomes of adults with idiopathic thrombocytopenic purpura (ITP), we performed a follow-up study in a cohort of 152 consecutive patients who were treated according to a well-defined algorithm. Long-term outcomes were determined relative to the response 2 years after diagnosis, because most (93%) patients who...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood.v97.9.2549
更新日期:2001-05-01 00:00:00